Topic B Flashcards
1
Q
What are the essential functions of cell to cell communication?
A
- Regulation of development and organisation of cells into tissues
- Control of death, growth and division of cells
- Coordination of a diverse range of cellular activities
2
Q
What are the 3 types of hormones and examples:
A
- Polypeptide/protein hormones:
- stored in secretory vesicles for up to 1 day as pro-hormones
- secretion is regulated by other hormones
- circulate free in the blood
- bind to cell-surface receptors
- relatively short lifespan= minutes
e. g. insulin, glucagon, leptin, growth hormone - Peptide-amine hormones:
- derived from the amino acid tyrosine
e. g. epinephrine and norepinephrine:
- synthesised in adrenal medulla and CNS
- stored in vesicles for several days
- secreted in response to signals from CNS
- free in blood
- bind to cell surface receptors
- very short lifespan (seconds)
e. g. thyroid hormones- T3 and T4:
- synthesised in thyroid gland
- lipophilic- bind intracellular receptors - Lipophilic hormones:
e. g. steroid hormones: testosterone, estradiol and cortisol
e. g. vitamin D
- bind intracellular receptors
- transported in blood attached to plasma proteins
- longer lifespan
3
Q
What are nuclear receptors?
A
- intracellular receptors that mediate signals from lipophilic ligand (e.g. steroid hormones, thyroid hormones) and transmit the signal to the nucleus of the cell to alter gene expression and physiology
- many nuclear receptors function as ligand-dependent transcription factors
4
Q
Describe a nuclear receptor structure:
A
- DNA binding domain: e.g. zinc fingers; that will bind with the major groove of DNA
- Transcription activating domains: that bind other molecules that help regulate gene expression such as coactivator proteins
- Ligand binding domain: binding of the ligand to this domain leads to a confirmational change allowing DNA binding and transcription activating domains to bind their targets; binding of ligand may remove inhibitory protein complexes
5
Q
What is the basic function of a nuclear receptor?
A
- Bind ligand within the cytoplasm or nucleus
- Ligand binding to the ligand binding domain causes the receptor to translocate to the nucleus (if not already there)
- The ligand binding the ligand binding site causes a confirmational change in the receptor- inhibitory proteins are removed, coactivator proteins attach to the transcription-activating domain and the DNA binding domain binds to the target DNA
6
Q
What is a SERM/SARM?
A
SERMs= selective estrogen receptor modulators SARMs= selective androgen receptor modulators
7
Q
How do SERMs/SARMs work?
A
- These molecules bind to estrogen receptors/androgen receptors an recruit different co-activators/co-repressors (usually co-repressors) and thus alter the effect the activation of the ER/AR has on genes. They can be agonists (upregulate the receptor activity) or antagonists (downregulate receptor activity) depending on cell type or tissue
8
Q
Why is the drug Tamoxifen perhaps not a good choice for treating advanced breast cancer?
A
- Tamoxifen is a ER antagonist in breast tissue that prevents estrogen signalling and thus prevents proliferation of some breast cancers- however it is a ER agonist in endometrium and it may promote tumour growth.
9
Q
For treating breast/prostate cancer what other treatments other than SERMs/SARMs are used?
A
- Targeting the production of the ER/AR ligand e.g. estrogen/testosterone via inhibiting enzymes
10
Q
What is a G-coupled protein receptor (GCPR)?
A
- A large cell surface receptor with 7 membrane spanning segments that interacts directly with a trimeric GTP-binding protein (G-protein)
- When the ligand binds to the extracellular receptor domain it activates the G-protein and the G-protein goes onto active a cascade of second messengers
e. g. beta-adrenergic receptors
11
Q
How does GPCR activation occur?
A
- Ligand binds with GPCR on the extracellular domain
- Receptor changes confirmation and interacts with the inactive GDP bound G-protein
- Causes the G-protein to eject GDP for GTP which induces a confirmational change in the G-protein causing it to release the receptor
- The activated G-protein activates a range of second messengers including adenylyl cyclase which causes the conversion of ATP -> cAMP
- cAMP activates protein kinase which phosphorylates many other proteins which induces a change in the cell
12
Q
What are 5 ways to down-regulate GPCRs?
A
- Receptor sequestration (receptor and ligand ingested into endosome- ligand removed- receptor returned to cell surface)
- Down-regulation of receptor (receptor and ligand ingested into endosome and broken down by lysosome)
- Receptor inactivation
- Inactivation of signalling proteins
- Introduction of inhibitory proteins
13
Q
What is an enzyme coupled receptor?
A
- A cell-surface receptor where the extracellular domain of the enzyme binds a ligand and becomes a dimer (thus activated) which in turn activates a sequence of second messengers that can alter cytosolic proteins or act on DNA to induce/repress gene expression
14
Q
What are the 3 main families of enzyme coupled receptors?
A
- Receptor tyrosine kinases
- Tyrosine-kinase associated receptors
- Receptor serine/threonine kinases
15
Q
How do receptor tyrosine kinases work?
A
- The signal molecule e.g. a growth factor will bind the exracellular domain of an inactive monomer RTK causing it to become dimerised
- The dimerization brings the two tyrosine kinase domains of the RTKs together causing them to autophosphorylate and activate
- The activated tyrosine kinase domains cause the C terminus tails of the dimer tyrosine residues to become autophosphorylated
- This creates new binding sites- the specificity of which are determined by the amino acids residues surrounding the phosphorylated tyrosine residues- for signalling proteins to bind to and become activated via phosphorylation e.g. RAS, PI-3 kinase etc.
16
Q
What is the Ras Family of GTPases? What do they relate to?
A
- A common family of downstream signalling proteins activated by the signalling cascade of RTKs
- A monomeric GTP protein that oscillates between inactivate (GDP bound form) and active (GTP bound form)
- Provides a crucial link in the intracellular signalling cascade of RTKs
17
Q
Give an example of an RTK signalling cascade involving Ras:
A
- RTK binds signalling molecule and becomes dimerised activating the tyrosine kinase domain causing an auto phosphorylation of the C terminal tail tyrosine residues
- A secondary adaptor protein binds via its SH2 domain to the phosphorylated tyrosine residue(s) on the activated RTK
- The SH3 domain of this secondary protein that is also bound to the activated RTL will bind to a Ras-GEF protein (guanine exchange protein) activating it
- The Ras-GEF protein stimulates the exchange of the GDP on an inactive Ras protein for a GTP which in turn activates the Ras protein causing a conformational change and allows for a series of downstream signals including the MAP kinase pathway
18
Q
What is the MAP kinase pathway?
A
- A signalling pathway activated by the activation of Ras protein as part of a RTK signalling cascade
- It is a serine/threonine signalling cascade:
1. Activated Ras protein will activate the MAP kinase kinase kinase (Raf) which is a serine/threonine kinase that phosphorylates MAP kinase kinase (Mek)
2. Phosphorylation activates Mek and causes it to phosphorylate the serine/threonine residues of the MAP kinase (Erk)
3. Erk goes onto phosphorylate a number of cellular proteins resulting in changes in protein activity and changes in gene expression - This Ras-Raf-Mek-Erk signalling pathway can be inhibited- used to treat cancer and disease
19
Q
What are receptor serine/threonine kinases?
A
- These receptors bind signal molecules such as TGF-B and act via the following mechanism:
1. Binding of the signal e.g. a growth factor, causes the dimerization of two receptors which results in activation of the serine/threonine kinase domains
2. This triggers the binding of the secondary protein e.g. Smads which bind to the tail of the receptor and become phosphorylated and detach forming a trimer complex
3. This Smad protein complex moves into the nucleus and acts as a transcription regulatory complex
20
Q
What is the difference between type I and type II diabetes Mellitus?
A
Type I diabetes:
- Also known as juvenile diabetes and insulin dependent diabetes mellitus (IDDM)
- An autoimmune disease in which there is a destruction of insulin producing beta cells in the pancreas
Type II diabetes:
- Much more prevalent in Australia (90% of diabetes cases)
- Also known as non-insulin dependent diabetes mellitus (NIDDM)
- The cells of the body are resistant to the effects of insulin and ultimately there will be impaired insulin production
21
Q
How insulin synthesised and stored?
A
- Insulin is produced by B cells of the islets of Langerhans in the pancreas
- Syntheised as a preprohormone is is cleaved to produce proinsulin
- It is stored as proinsulin in vesicles until a singal (high levels of circulating blood glucose) causes them to be secreted into the blood stream
22
Q
How does the secretion of insulin occur?
A
- When blood glucose is high e.g. after a meal GLUT 2 receptors (which have a high Km) will transport glucose into the pancreatic β cells
- When glucose is transported into the cell if it is in high enough concentrations it will be converted to glucose 6 phosphate by hexokinase IV and then it will move down the glycolytic pathway, CAC and the ETC leading to the production of ATP
- An increase in ATP levels in the pancreatic β cells close ATP gated K+ channels in the plasma channels in the cell membrane, leading to a depolarisation of the cell membrane
- The depolarisation triggers the opening of a voltage dependent Ca2+ channel causing an influx of calcium into the cell and a increase in intracellular calcium levels
- The increase in cytosolic calcium levels also causes the release of calcium from the ER of the cell leading to a further increase in cytosolic calcium
- The high calcium levels triggers the secretion of insulin from the cell
23
Q
How does insulin affect fatty acid synthesis?
A
- Insulin stimulates the entry of glucose into the glycolytic pathway which results in the production of pyruvate which can be converted into acetyl-CoA which in turn is converted into fatty acids which can be used made into TAGs for efficient storage
- A lack of insulin leads to an increase in lipolysis and a failure to synthesise FAs
- This also elevates ketone levels
24
Q
Describe the effect of Type I diabetes on lipid metabolism:
A
- No stimulation of the uptake of TAGs by adipocytes
- No stimulation for conversion of FAs to TAGs
- No inhibition for the breakdown of TAGs to fatty acids and glycerol
- There is an elevation of lipids in the blood stream
